Genetic Variant GIGYF2:c.268-9_268-6dupTTTT (chr2-232756197-C-CTTTT) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001103146.3(GIGYF2):c.268-9_268-6dupTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0020 ( 2 hom. )

Consequence

GIGYF2
NM_001103146.3 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.876

Publications

0 publications found

Variant links:

Genes affected

GIGYF2 (HGNC:11960): (GRB10 interacting GYF protein 2) This gene contains CAG trinucleotide repeats and encodes a protein containing several stretches of polyglutamine residues. The encoded protein may be involved in the regulation of tyrosine kinase receptor signaling. This gene is located in a chromosomal region that was genetically linked to Parkinson disease type 11, and mutations in this gene were thought to be causative for this disease. However, more recent studies in different populations have been unable to replicate this association. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

GIGYF2 Gene-Disease associations (from GenCC):

Parkinson disease 11, autosomal dominant, susceptibility to
Inheritance: AD, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

GIGYF2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 34 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GIGYF2	NM_001103146.3 link	c.268-9_268-6dupTTTT		splice_region_variant, intron_variant	Intron 5 of 28	ENST00000373563.9	NP_001096616.1	Q6Y7W6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GIGYF2	ENST00000373563.9 link	c.268-26_268-25insTTTT		intron_variant	Intron 5 of 28	1	NM_001103146.3	ENSP00000362664.5		Q6Y7W6-1

Frequencies

GnomAD3 genomes

AF:

0.000331

AC:

AN:

102712

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000269

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000358

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.000272

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000418

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00202

AC:

1226

AN:

606668

Hom.:

Cov.:

AF XY:

0.00215

AC XY:

693

AN XY:

321640

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00189

AC:

AN:

14848

American (AMR)

AF:

0.00218

AC:

AN:

25734

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

16038

East Asian (EAS)

AF:

0.00130

AC:

AN:

31426

South Asian (SAS)

AF:

0.00583

AC:

280

AN:

48036

European-Finnish (FIN)

AF:

0.000812

AC:

AN:

36968

Middle Eastern (MID)

AF:

0.00265

AC:

AN:

2266

European-Non Finnish (NFE)

AF:

0.00171

AC:

688

AN:

401696

Other (OTH)

AF:

0.00202

AC:

AN:

29656

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.351

Heterozygous variant carriers

136

203

271

339

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000331

AC:

AN:

102678

Hom.:

Cov.:

AF XY:

0.000294

AC XY:

AN XY:

47566

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

26040

American (AMR)

AF:

0.00

AC:

AN:

8742

Ashkenazi Jewish (ASJ)

AF:

0.000358

AC:

AN:

2792

East Asian (EAS)

AF:

0.00

AC:

AN:

3746

South Asian (SAS)

AF:

0.00104

AC:

AN:

2896

European-Finnish (FIN)

AF:

0.000272

AC:

AN:

3678

Middle Eastern (MID)

AF:

0.00

AC:

AN:

152

European-Non Finnish (NFE)

AF:

0.000418

AC:

AN:

52574

Other (OTH)

AF:

0.00

AC:

AN:

1330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.434

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

144

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.88

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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2-232756197-CTTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over